Immunostimulatory agonistic antibodies for use in treating cancer

Abstract

Provided herein are methods of treating cancer using agonistic antibodies that specifically bind to immunostimulatory receptors, wherein the antibodies are administered in an amount and/or frequency sufficient to achieve and/or maintain a receptor occupancy of less than about 80%, for example, a receptor occupancy of about 20% to about 80%. Also provided are methods of determining human doses for such agonistic antibodies, and methods for monitoring receptor occupancy of the agonistic antibodies in order to maintain effective antibody levels in, e.g., human patients.

We claim: 
     
         1 . A method of (i) treating a cancer in a subject in need thereof, (ii) reducing or depleting the number of regulatory T cells in a tumor of a subject with a cancer, (iii) increasing IL-2 and/or IFN-yproduction in T cells of a subject with a cancer, (iv) stimulating an immune response in a subject with a cancer, (v) inhibiting the growth of tumor cells in a subject with cancer, or (vi) combinations thereof, comprising administering to the subject an agonistic antibody that specifically binds to an immunostimulatory receptor, wherein the agonistic antibody is administered at a dose and/or frequency that is sufficient to achieve and/or maintain a receptor occupancy of about 20% to about 80% in the subject. 
     
     
         2 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the immunostimulatory receptor is selected from the group consisting of a member of tumor necrosis factor receptor superfamily (TNFRSF), ICOS (CD278), CD28, LIGHT, CD40L, TIM1, SLAM, CD1, CD2, CD226, LFA-1 (CD11a/CD18), CD2, CD7, CD30, CD40, CD54, CD160, BAFFR, HVEM, LIGHT, NKG2C, SLAMF7, and NKp80. 
     
     
         13 . The method of  claim 1 , wherein the agonistic antibody comprises an anti-OX40 antibody. 
     
     
         14 - 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: a bladder cancer, a breast cancer, an uterine/cervical cancer, an ovarian cancer, a prostate cancer, a testicular cancer, an esophageal cancer, a gastrointestinal cancer, a pancreatic cancer, a colorectal cancer, a colon cancer, a kidney cancer, a head and neck cancer, a lung cancer, a stomach cancer, a germ cell cancer, a bone cancer, a liver cancer, a thyroid cancer, a skin cancer, a neoplasm of the central nervous system, a lymphoma, a leukemia, a myeloma, a sarcoma, a non-small cell lung cancer, and a virus-related cancer. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 13 , further comprising administering one or more additional therapies selected from an anti-PD1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, an anti-PD-L1 antibody, an anti-TGFβ antibody, or combinations thereof. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 22 , wherein the one or more additional therapies comprises an anti-PD1 antibody. 
     
     
         25 . The method of  claim 22 , wherein the agonistic antibody is administered (i) before administration of the one or more additional therapies, (ii) after administration of the one or more additional therapies, or (iii) concurrently with the one or more additional therapies. 
     
     
         26 - 28 . (canceled) 
     
     
         29 . A method of selecting an effective dose and/or administration schedule for an agonistic antibody that specifically binds to an immunostimulatory receptor and that can be used for the treatment of a subject with a cancer comprising.
 selecting the dose and/or administration schedule for the agonistic antibody that is sufficient to achieve and/or maintain a receptor occupancy of about 20% to about 80% in the subject.   
     
     
         30 - 35 . (canceled) 
     
     
         36 . A method of detecting the level of a therapeutic an agonistic antibody after administration to a subject with a cancer, wherein the agonistic antibody specifically binds to an immunostimulatory receptor, comprising: 
 (a) determining the receptor occupancy of the agonistic antibody in a sample obtained from the subject; and   (b) administering a reduced dose and/or frequency of the agnostic antibody to the subject if the receptor occupancy is greater than about 80%, or administering an increased dose and/or frequency of the agonistic antibody if the receptor occupancy is less than about 20%.   
     
     
         37 - 48 . (canceled) 
     
     
         49 . The method of  claim 22 , wherein the one or more additional therapies are administered at a fixed frequency. 
     
     
         50 - 52 . (canceled) 
     
     
         53 . A method of determining the effectiveness of an anti-cancer treatment in a subject in need thereof comprising measuring levels of soluble OX40 in the subject wherein the anti-cancer treatment comprises administering an agonistic antibody that specifically binds to an immunostimulatory receptor to the subject. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 24 , comprising at least one administration cycle of a combination of an anti-OX40 antibody and an anti-PD1 antibody, wherein each of the at least one administration cycle is a period of twelve weeks, and wherein each of the at least one administration cycle comprises one administration of the anti-OX40 antibody at a dose of 20, 40, or 80 mg and three administrations of the anti-PD-1 antibody at a dose of 480 mg. 
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 55 , wherein the anti-PD-1 and anti-OX40 antibodies are formulated for intravenous administration. 
     
     
         58 . The method of  claim 55 , wherein the anti-PD-1 and anti-OX40 antibodies are formulated together or separately. 
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 55 , wherein the anti-OX40 antibody is administered (i) prior to administration of the anti-PD-1 antibody (ii) after administration of the anti-PD-1 antibody, or (iii) concurrently with the anti-PD-1 antibody. 
     
     
         61 - 63 . (canceled) 
     
     
         64 . The method of  claim 55 , consisting of up to 9 administration cycles. 
     
     
         65 . The method of  claim 55 , wherein the anti-OX40 antibody is administered on Day 1 of each of the at least one administration cycle. 
     
     
         66 . The method of  claim 55 , wherein the anti-PD-1 antibody is administered on Days 1, 29, and 57 of each of the at least one administration cycle. 
     
     
         67 - 69 . (canceled) 
     
     
         70 . The method of  claim 55 , wherein the anti-OX40 antibody comprises 
 (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:_5;   (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:_6;   (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:_7;   (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:_8;   (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:_9; and   (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:_10.   
     
     
         71 - 72 . (canceled) 
     
     
         73 . The method of  claim 55 , wherein the anti-PD-1 antibody comprises 
 (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:_20;   (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:_21;   (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:_22;   (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:_23;   (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:_24; and   (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:_25.   
     
     
         74 - 75 . (canceled)